Possible Potentiation by Certain Antioxidants of the Anti-Inflammatory Effects of Diclofenac in Rats

In the present study, we investigated the potential beneficial impact of the addition of antioxidant supplements to diclofenac regimen in a model of carrageenan-induced paw. Rats were treated daily with antioxidants, that is, a-lipoic acid (50 mg/kg), selenium (2.5 mg/kg), vitamin C (1 g/kg), vitamin E (300 mg/kg), or zinc (25 mg/kg) on seven successive days and then received a single treatment with diclofenac or saline before carrageenan was injected to induce paw inflammation. The results indicated that these combinations did not significantly affect the percentage inhibition of paw edema caused by diclofenac alone; however, some combination treatments ameliorated signs of concomitant oxidative stress (such as alterations in plasma malondialdehyde (MDA) levels, hemolysate reduced glutathione levels, and erythrocytic superoxide dismutase enzyme activities) imparted by diclofenac alone. In some cases, few tested antioxidants in combination with diclofenac resulted in increased plasma levels of interleukin- (IL-) 6 and C-reactive protein (CRP). In conclusion, the results of these studies suggested to us that the added presence of natural antioxidants could be beneficial as standard anti-inflammatory therapeutics for a patient under diclofenac treatment, albeit that these effects do not appear to significantly build upon those that could be obtained from this common anti-inflammatory agent per se

Immunomodulatory effect of Premna odorata volatile oils in Mycobacterium tuberculosis by inhibiting TLR4/NF-κB pathway

Introduction: The development of multi drug resistant (MDR) tuberculosis (TB) and extensively drug resistant (XDR) TB, increased the interest in the usage of medicinal plants that are complementary to antibiotics to improve anti-TB efficacy. The present study aimed to confirm the anti-TB efficacy of volatile oils (VOs) isolated from different parts of Premna odorata in vivo, and moreover, to test the possible involvement of TLR4/NF-κB signaling pathway in its anti-TB efficacy. Methods: Thirty mice were divided into six equal groups. Group 1: healthy mice (negative control). Groups 2-6 were injected intravenously with a positive TB solution of purified MeDiPro Mycobacterium tuberculosis (MTB) antigen for 7 days to induce tuberculosis. Group 3-6: TB-injected mice treated respectively with leaves VO (300 μL/d), young stems VO (300 μL/d), flowers VO and a combination of the three essential VOs (1:1:1). Various immunologic factors and antioxidant activity were evaluated and compared in the groups. Results: TB-infected mice showed a significant increase in the serum levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), interleukin (IL) 1-β and the mRNA expression levels of toll-like receptor 4 (TLR-4) & nuclear factor-κB (NF-κB) and a decrease in IL-10 & total antioxidant capacity (TAC). While pretreatment with VOs extracted from leaves, flowers, young stems and a combination of the three oils reversed these effects. Conclusion: The immunomodulatory effects of VOs extracted from different parts of P. odorata against TB infection involve the TLR-4/NFκB signaling pathway as well as, antioxidant effects, recommending that the use of this plant may help TB infected patients

The cardioprotective effects of secoisolariciresinol diglucoside (flaxseed lignan) against cafeteria diet-induced cardiac fibrosis and vascular injury in rats: an insight into apelin/AMPK/FOXO3a signaling pathways

Introduction: Fast food is a major risk factor for atherosclerosis, a leading cause of morbidity and mortality in the Western world. Apelin, the endogenous adipokine, can protect against cardiovascular disease via activating its receptor, APJ. Concurrently, secoisolariciresinol diglucoside (SDG), a flaxseed lignan extract (FLE), showed a therapeutic impact on atherosclerosis. The current study aimed to examine the effect of SDG on cafeteria diet (CAFD)-induced vascular injury and cardiac fibrosis via tracking the involvement of the apelin/APJ pathway.Methods: Thirty male rats were allocated into control, FLE-, CAFD-, CAFD/FLE-, and CAFD/FLE/F13A-treated rats, where F13A is an APJ blocker. All treatments lasted for 12 weeks.Results and discussion: The CAFD-induced cardiovascular injury was evidenced by histological distortions, dyslipidemia, elevated atherogenic indices, cardiac troponin I, collagen percentage, glycogen content, and apoptotic markers. CAFD increased both the gene and protein expression levels of cardiac APJ, apelin, and FOXO3a, in addition to increasing endothelin-1, VCAM1, and plasminogen activator inhibitor-1 serum levels and upregulating cardiac MMP-9 gene expression. Moreover, CAFD reduced serum paraoxonase 1 and nitric oxide levels, cardiac AMPK, and nuclear Nrf2 expression. FLE attenuated CAFD-induced cardiovascular injury. Such effect was reduced in rats receiving the APJ blocker, implicating the involvement of apelin/APJ in FLE protective mechanisms.Conclusion: FLE supplementation abrogated CAFD-induced cardiac injury and endothelial dysfunction in an apelin/APJ-dependent manner

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

Antidiabetic efficacy of lactoferrin in type 2 diabetic pediatrics; controlling impact on PPAR-γ, SIRT-1, and TLR4 downstream signaling pathway

Abstract The current study aims to investigate the antidiabetic efficacy of camel milk-derived lactoferrin and potential involvement of PPAR-γ and SIRT-1 via TLR-4/NFκB signaling pathway in obese diabetic pediatric population. Sixty young obese patients with type 2 diabetes were selected from the Pediatric Endocrine Metabolic Unit, Cairo University and were randomly divided among two age and sex-matched groups so as to receive either standard therapy without lactoferrin in one arm or to be treated with oral lactoferrin capsules (250 mg/day, p.o) for 3 months in the other arm. Both groups were compared to 50 control healthy volunteers. Measurements of HbA1c, lipid profile, antioxidant capacity (SOD, Nrf2), proinflammatory interleukins; (IL-1β, IL-6, IL-18), Cyclin D-1, lipocalin-2, and PPAR-γ expression levels were done at the beginning and 3 months after daily consumption of lactoferrin. The mechanistic involvement of TLR4-SIRT-1-NFκB signaling cascade was also investigated. The antidiabetic efficacy of lactoferrin was confirmed by significant improvement of the baseline levels of HbA1c, BMI and lipid profile of the obese pediatric cohort, which is evidenced by increased PPAR-γ and SIRT-1 expression. Moreover, the anti-inflammatory effect was evident by the significant decrease in serum levels of IL-1β, IL-6, IL-18, TNF-α, lipocalin 2 in type 2 diabetic post-treatment group, which corresponded by decreased NFκB downstream signaling indicators. The antioxidant efficacy was evident by stimulated SOD levels and NrF2 expression; compared with the pre-treatment group (all at P ≤ 0.001). The consumption of high concentrations of lactoferrin explains its hypoglycemic efficacy and counts for its insulin-sensitizing, anti-inflammatory and immunomodulatory effects via TLR4-NFκB-SIRT-1 signaling cascade. Recommendations on regular intake of lactoferrin could ensure better glycemic control, compared to conventional antidiabetics alone

Effect of topiramate on serum biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on serum (A) triglycerides (TGs, [mg/dl]), (B) total cholesterol(TC, [mg/dl]), (C) free fatty acids (FFAs, mmol/l]), (D)ALT (IU/L), (E) tumor necrosis alpha (TNF-α, [pg/ml]) and (F) adiponectin [ng/ml] of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM40 ^(<b>‡</b>) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Correlation coefficient (<i>r</i>) between HOMA-I and serum adiponectin with hepatic GLUT2, adiponectin receptors (Adipo- R1, R2), insulin receptor isoforms (LAIR, HAIR), and tyrosine kinase.

<p>Correlation was carried out in untreated and treated hyperglycemic animals.</p

The glucose tolerance test (GTT).

<p>The curve depicts the changes in serum glucose response in normal control, non-treated obese/insulin-resistant rats (HFFD), and treated ones by either dose of topiramate (40 & 100 mg/kg;HFFD+TPM40, HFFD+TPM₁₀₀), after 0, 30, 60, 90, and 120 min following administration of glucose (2 g/kg, ip). Values are means (± S.D) of 10 animals; as compared with normal control (^*), and HFFD (<b>^†</b>) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on hepatic biomarkers.

<p>The panels illustrate the effect of topiramate (40 & 100 mg/kg, p.o; TPM₄₀, TPM₁₀₀) on hepatic (A, B) insulin receptor isoforms (high affinity, [HAIR, fmol/mg protein] and low affinity [LAIR, pmol/mg protein] insulin receptor), (C, D) adiponectin receptors (Adipo-R1, Adipo-R2 [ng/mg protein]), (E) protein tyrosine kinase (PTK [U/mg protein]), and (F) glucose transporter-2 (GLUT2 [mg/mg protein]) of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks (mean of 10 animals ± S.D.). Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM40 ^(‡) groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p

Effect of topiramate on the indicators of glucose homeostasis of obese/insulin resistant rats.

<p>Effect of topiramate (40, 100 mg/kg; TPM₄₀, TPM₁₀₀) on serum levels of glucose, insulin, and fructosamine, HOMA-index and area under the curve of the GTT of obese/insulin resistant rats fed high fat and high fructose diet [HFFD] for 10 weeks. Values are means (± S.D.) of 10 animals. Treatments were administered once daily for 2 weeks. As compared with normal control (^*), HFFD (<b>^†</b>) and HFFD+TPM₄₀<b>(^‡)</b> groups (one-way ANOVA followed by Tukey–Kramer Test), <i>P</i><0.05.</p